Interesting Cases in HIV Medicine Jehan Budak, MD Medical - PDF document

12/14/19 Interesting Cases in HIV Medicine Jehan Budak, MD Medical Management of HIV/AIDS December 14, 2019 jehan@uw.edu 1 Disclosures • I have nothing to disclose. 2 1

12/14/19 Roadmap • ART with M184V • Anticoagulants and ART • Doravirine as Salvage • A Modern Toxo Tale 3 Roadmap • AR ART T with M184V • Anticoagulants and ART • Doravirine as Salvage • A Modern Toxo Tale 4 2

12/14/19 Case 1 5 Case 1 • 53M with HIV comes in for regularly scheduled follow-up • Last CD4 683 cells/mm 3 , HIV RNA <40 copies/mL • On TAF/FTC/RPV + DTG since 2016 • HIV History • Diagnosed 12/2002, started 3TC/AZT + NFV, complicated by nausea/vomiting • 4/2003 HIV RNA 16K copies/mL, genotype with M184V mutation • Switched to new regimen and HIV RNA has been suppressed since then • He has been hesitant to simplify his ART 6 3

12/14/19 ARS: What would you do with his ART in light of the M184V? A. Continue current regimen (TAF/FTC/RPV + DTG) B. Simplify to TAF/FTC/RPV alone C. Switch to TAF/FTC + DTG D. Switch to BIC/TAF/FTC E. Switch to TAF/FTC/c/DRV F. Switch to ABC/3TC/DTG 7 What would you do with his ART in light of the M184V? A. Continue current regimen (TAF/FTC/RPV + DTG) B. Simplify to TAF/FTC/RPV alone C. Switch to TAF/FTC + DTG D. Switch to BIC/TAF/FTC What is the data for E. Switch to TAF/FTC/c/DRV use of these ARVs F. Switch to ABC/3TC/DTG with an M184V? 8 4

12/14/19 Option C: Switch to TAF/FTC + DTG • Background • DAWNING (IAS 2017): In 627 patients worldwide failing NNRTI therapy, when paired with ≥ 1 active NRTI, DTG was superior to r/LPV as salvage • DAWNING sub-analysis (CROI 2019): Looked at different NRTI mutations and the impact of those mutations on ≥ 1 active NRTI + DTG or r/LPV • Patients were NOT virologically suppressed before starting the study but did have genotypes (GT) available Aboud M, IAS 2017 #5613; Brown D, CROI 2019 #144. 9 DAWNING Sub-Analysis: Virologic outcomes 62 M184V absent 80 72 M184V present 84 70 Overall 84 0 10 20 30 40 50 60 70 80 90 % with HIV-1 RNA < 50 copies/mL Brown D, CROI 2019 #144. 10 5

12/14/19 DAWNING Sub-Analysis: Results • DTG maintained virologic suppression when paired with 2 NRTIs regardless of pre-existing RAM to one of the NRTIs (i.e. ≥ 1 active NRTI) • Virologic failure lower in DTG arm (11) than r/LPV arm (30) • RAMs emerged in 2 in DTG and 3 in PI arm • DTG failures: INSTI-R (G118R, R263K) • r/LPV failures: No PI-R • Reaffirms that DTG can fail with INSTI resistance, but b/PIs generally do not Brown D, CROI 2019 #144. 11 Option D: Switch to BIC/TAF/FTC • Background • BIC/TAF/FTC (Biktarvy) has been found to be non-inferior in • Treatment-naïve individuals (Studies 1489, 1490) 1,2 • As switch in virologically suppressed individuals (Studies 1844, 1878) 3,4 • Women (1961) 5 • But what about its use in people with underlying resistance? 1-Gallant J, Lancet HIV 2017. 2-Sax P, Lancet HIV 2017.3-Molina JM, Lancet HIV 2018. 4-Daar E, Lancet HIV 2018. 5-Kityo, CROI 2018 #500. 12 6

12/14/19 Switch to BIC/TAF/FTC in Patients with Historical Resistance • Study GS-4030: Placebo-controlled RCT of 565 virologically suppressed patients on TAF/FTC + DTG or TDF/FTC + DTG randomized to continue regimen or switch to BIC/TAF/FTC • Genotypic data obtained from historical + archived GT • Baseline NRTI-R in 24% of the study (138/565), including M184V in 14% of study (81/565) • 48 Week Results • Overall, 93 vs 91% virologic suppression overall • 98% with M184 (81) maintained suppression • No treatment-emergent resistance Acosta R, CROI 2019 #551 and IAS 2019 #MOPEB241. 13 Historical Resistance in Switch Studies 1844 + 1878 • OLE of 570 patients to evaluate virologic outcomes based on analysis of pre-existing resistance from historical and archived GT (543/570) • Overall, 16% (89/543) had NRTI resistance, with M184 in 10% (54/543) • 48 Week Results • Overall, 98% of B/F/TAF-treated participants were suppressed • 96% (52/54) with archived M184 were suppressed Andreatta K, JAC 2019. 14 7

12/14/19 Option E: Switch to TAF/FTC/c/DRV • Background • TAF/FTC/c/DRV (Symtuza) was FDA approved July 2018 • EMERALD Study • Randomized controlled trial switch study of 1,141 virologically suppressed to TAF/FTC/c/DRV vs continued TDF/FTC + b/DRV (non-inferior) • 58% had ≥ 5 prior ARV regimens • 15% with previous virologic failure but not to DRV • Resistance allowed, but not to DRV (4% with M184 but on archived GT) Orkin C, Lancet HIV, 2018; Lathouwers E, HIV Glasgow 2018 #P294. 15 ART with M184V: Take-home points 1. DAWNING subanalysis affirms the practice of using DTG with <2 active NRTIs, but ≥ 1 active NRTI (to avoid DTG monotherapy) 2. If already suppressed with baseline M184, can likely switch to BIC/TAF/FTC and stay virologically suppressed 3. TAF/FTC/c/DRV is a good option for the heavily treatment experienced with M184 and other baseline RAMs (but not to DRV) 16 8

12/14/19 Roadmap • ART with M184V • An Anticoagu gulants and AR ART • Doravirine as Salvage • A Modern Toxo Tale 17 Case 2 18 9

12/14/19 Case 2 • 61M with HIV presents to urgent care with RLE swelling • Last CD4 348 cells/mm 3 , HIV RNA <40 copies/mL • Diagnosed with acute unprovoked DVT, needs anticoagulation • On ABC/3TC/r/DRV since 2016 19 ARS: Which regimen will you use if he is unable to switch his ART regimen? A. Warfarin B. Apixaban C. Dabigatran D. Rivaroxaban 20 10

12/14/19 Background • Direct-acting oral anticoagulant (DOAC) use is increasing • Commonly used DOACs - apixaban, rivaroxaban, and dabigatran – are eliminated either via CYP450 enzymes, P-glycoprotein, or both • Warfarin is metabolized by CYP2C9 Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum. 21 ART & Anticoagulants DOAC Warfarin Apixaban Rivaroxaban Dabigatran ✓ ✓ ✓ ✓ NRTI Caution Caution Caution Caution NNRTI ✕ ✕ ✕ PI Caution ✓ ✓ ✓ ✓ INSTI *except c/EVG Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum. 22 11

12/14/19 ART & Anticoagulants DOAC Warfarin Apixaban Rivaroxaban Dabigatran NRTI NNRTI PI INSTI *except c/EVG Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum. 23 NNRTIs & Anticoagulants DOAC Warfarin Apixaban Rivaroxaban Dabigatran NNRTI • CYP450 enzyme induction by NNRTIs may DECREASE levels of the DOAC • NNRTIs can alter warfarin levels Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum. 24 12

12/14/19 Protease Inhibitors & Anticoagulants DOAC Warfarin Apixaban Rivaroxaban Dabigatran PI • PIs can alter warfarin levels • CYP450 inhibition by PIs or boosters may INCREASE levels of the DOAC • Adult and Adolescent ARV Guidelines recommend avoiding DOACs + PIs Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum. 25 ARS: Which regimen will you use if the patient cannot switch ART and cannot adhere to INR monitoring? A. Warfarin B. Apixaban C. Dabigatran D. Rivaroxaban 26 13

12/14/19 But what if you HAVE to use a PI and a DOAC? • Rivaroxaban • Co-administration not been studied 1 • Apixaban • 50% dose reduction is recommended with close monitoring for bleeding • No adverse outcomes in 6 PWH on half-dose apixaban while on ritonavir- or cobicistat-boosted regimens 3 • Dabigatran • Dabigatran administered 2 hours before ritonavir 100mg resulted in dabigatran AUC decrease by 29%, so requires taking PI simultaneously with dabigatran 2 • Cobicistat 150mg with dabigatran increased dabigatran AUC by > 2-fold 4 1-Liverpool HIV Drug Interactions; 2-National HIV Curriculum; 3-Nisly SA, Int J STD AIDS, 2019; 4-AIDSinfo.gov 27 Take-Home Points • In general, NRTIs and INSTIs (except EVG) ok with DOACs and warfarin • NNRTIs and PIs can alter warfarin levels • NNRTIs can decrease DOAC levels – use caution • PIs generally increase DOAC levels – avoid • If have to use apixaban, use half-dose • May be able to use dabigatran • Do not use cobicistat with dabigatran • If using ritonavir with dabigatran, take PI and dabigatran simultaneously Oral Anticoagulants and Antiplatelet Therapy. National HIV Curriculum. 28 14

12/14/19 Roadmap • ART with M184V • Anticoagulants and ART • Do Doravirine as as Salv Salvag age • A Modern Toxo Tale 29 Case 3 30 15

12/14/19 Case 3 • 65M with HIV and multiple medical problems comes in for follow-up • Last CD4 388 cells/mm 3 , HIV RNA undetectable • On BIC/TAF/FTC + Doravirine Is this the best regimen for him? 31 Case 3: Prior Genotype Results • RT: M41L, K103N, Y181C, M184V, T215Y, H221Y • PI: None • INSTI: none M41L, T215Y (TAMs) – resistance to ABC and TDF/TAF M184V – resistance to ABC, 3TC, and FTC K103N – resistance to EFV and NVP Y181C – resistance to EFV, NVP, ETR, and RPV H221Y – some resistance to all NNRTIs Stanford HIV Drug Resistance Database. 32 16